Gastrointestinal (GI) motility results from the coordinated contractions of smooth muscle cells within the wall of the gut. At the heart of motility is electrical rhythmicity, a spontaneous property of GI smooth muscles that organizes contractile activity into phasic events. This project will continue to investigate the role of interstitial cells of Cajal (ICC) in the regulation of GI motility. We have identified specific populations of ICC within the colon and small bowel that provide pacemaker inputs to these organs. The present project will investigate the mechanisms of pacemaker action and attempt to determine the ionic basis for pacemaker function. We will study the role of ICC in propagation of electrical activity and the consequences of losing these cells. ICC have also been associated with neural control of GI muscles. We will investigate the anatomical relationships between ICC and nerve terminals of the enteric nervous system and determine what effects loss of ICC have on neurotransmission. These questions are particularly interesting and timely because several clinical disorders have now been associated with loss of ICC. In order to understand why ICC might be lost from GI tissues, we will investigate some of the factors regulating the development and plasticity of the ICC phenotype. We will investigate the tissue sources of stem cell factor, the ligand for the receptor tyrosine kinase c-Kit. Stem cell factor/c-Kit interactions define a critical signaling pathway for ICC development. An association between nerves and ICC has been suggested to be important during development. Therefore, we will study how the loss of intrinsic nerves affect ICC development morphology and function. We will determine the downstream pathways involved in c-Kit signaling and investigate whether disruption of signaling causes developmental failure or loss of IC from adult tissues. We will also study the fate of ICC when c-Kit signaling is blocked and determine how these cells change. Finally, we will study the long-term effects of induction of nitric oxide synthase in GI muscles and attempt to determine what tissue factors may contribute to protection of ICC in these muscles. This project should increase our knowledge of the role of ICC in GI motility and determine something of some these cells develop and respond to environmental stresses. If loss or disruption of ICC networks are significant factors in motility disorders, knowledge of what regulates the phenotypes of these cells may suggest new therapeutic approaches to common motility disorders.